Acquired resistance to anticancer treatments is a substantial barrier to reducing
Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy or acquired tolerance to AZD1152-HQPA anti-neoplastic treatments3 7 8 In addition the finding that assays of sensitivity to chemotherapy do not accurately predict responses indicate that tumor microenvironments also contribute substantially to cellular viability after toxic insults9-11. For example cell adhesion to matrix molecules can affect life and death decisions in AZD1152-HQPA tumor cells responding to damage12-14. Further the spatial organization of tumors relative to the vasculature establishes gradients of drug concentration oxygenation acidity and states of cell proliferation each of which Rabbit Polyclonal to ALK. may substantially influence cell survival and the subsequent tumor repopulation kinetics15 16 Most cytotoxic agents selectively target cancers by exploiting differential tumor cell characteristics such as high proliferation rates hypoxia and genome instability resulting in a favorable therapeutic index. However cancer therapies also affect benign cells and can disrupt the normal function and physiology of tissues and organs. To avoid host lethality most anticancer regimens do not rely AZD1152-HQPA on single AZD1152-HQPA overwhelming treatment doses: both radiation and chemotherapy are administered at intervals to allow the recovery of vital normal cell types. However gaps between treatment cycles also allow tumor cells to recover activate and exploit survival mechanisms and resist subsequent therapeutic insults. Here we tested the hypothesis that treatment-associated DNA damage responses in benign cells comprising the tumor microenvironment promote therapy resistance and subsequent tumor progression. We provide evidence of treatment-induced alterations in tumor stroma that include the expression of a diverse spectrum of secreted cytokines and growth factors. Among these we show that is activated in fibroblasts through NF-κB and promotes an epithelial to mesenchymal transition (EMT) in neoplastic prostate epithelium through paracrine signaling. Further WNT16B acting in a cell nonautonomous manner promotes the survival of cancer cells after cytotoxic therapy. We conclude that approaches targeting constituents of the tumor microenvironment in conjunction with conventional cancer therapeutics may enhance treatment responses. RESULTS Therapy induces damage responses in tumor microenvironments To assess for treatment-induced damage responses in benign cells comprising the tumor microenvironment we examined tissues collected before and after chemotherapy exposure in men with prostate cancer enrolled in a neoadjuvant clinical trial combining the genotoxic drug mitoxantrone (MIT) and the microtubule poison docetaxel (DOC) (Fig. 1a)17 18 After chemotherapy we found evidence of DNA damage in fibroblasts and smooth muscle cells comprising the prostate stroma as determined by the phosphorylation of histone H2AX on Ser139 (γ-H2AX) (Fig. 1b). To ascertain the molecular consequences of DNA damage in benign cells we treated primary prostate fibroblasts (PSC27 cells) with MIT bleomycin (BLEO) hydrogen peroxide (H2O2) or gamma radiation (RAD) each of which substantially increased the number of γ-H2AX foci (Supplementary Fig. 1a b). We used whole-genome microarrays to quantify transcripts in PSC27 cells and determined that the levels of 727 and 329 mRNAs were commonly increased and decreased respectively (false discovery rate of 0.1%) as a result of these genotoxic exposures (Supplementary Fig. 1c). To focus our studies on those factors with the clear potential for paracrine effects on tumor cells we evaluated genes with at least 3.5-fold elevated expression after genotoxic treatments that encode extracellular proteins here collectively termed the DNA damage secretory program (DDSP) (Fig. 1c). Consistent with previous studies transcripts encoding matrix metalloproteinases such as MMP1 chemokines such as CXCL3 and peptide growth factors such as amphiregulin were substantially elevated in PSC27 fibroblasts after.